During the follicular phase of the primate menstrual cycle a single pre- ovulatory follicle is selected to mature and release its oocyte for fertilization and initiation or pregnancy. While it is well established that the gonadotropic hormones follicle stimulating hormone (FSH) and luteinizing hormone (LH) are essential for successful follicular development, over the past decade, it has become evident that other non- gonadotropic factors can also influence ovarian function, either through direct actions on the ovary or by modifying the secretion of FSH and /or LH by the hypothalamic-pituitary axis. In particular, it is clear from a large number of in vitro studies that IGF-I, insulin and androgens play a role in ovarian function by augment (or perhaps inhibiting) the stimulatory actions of FSH and LH on follicular granulosa and theca cells respectively as well as by altering the patterns of FSH and LH secretion. While such actions have been well documented using in vitro approaches, to date their ability to influence the hypothalamic-pituitary-ovarian axis in vivo in primates has not been investigated. Accordingly, we propose to undertake a systematic analysis of the roles of IGF-I, insulin and androgen on the hypothalamic-pituitary-ovarian axis in subhuman primates. In Aim 1 we will test insulin and androgen on the hypothalamic-pituitary-ovarian axis in subhuman primates. In Aim 1 we will test 2, we will test the hypothesis that insulin, IGF-I and androgen influence the sensitivity of the ovarian vivo to FSH. In Aim 2, we will test the hypothesis that insulin, IGF-I and androgen alter the sensitivity of the hypothalamic-pituitary axis to the feedback inhibition of estrogen. In Aim 3 we will test the hypothesis that insulin, IGF-I and androgen alter ovarian cellular proliferation, differentiation and atresia by converging upon intracellular signaling systems that have recently been shown to govern cell proliferation and cell survival. Lastly, in Aim 4, we will determine the effects of insulin, IGF-I and testosterone on menstrual cyclicity in subhuman primates. It is expected that the results of these studies will provide novel information that will have direct bearing not only on normal ovarian function but also pathophysiological aspects of infertility in which normal development of follicles is impaired, especially polycystic ovarian syndrome but also pathophysiological aspects of infertility in which normal development of follicles is impaired, especially polycystic ovarian syndrome in humans which is associated with alterations in insulin sensitivity and altered androgen production.